CBLB Gene Editing in T Cells for Cancer Immunotherapy

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Solution Overview

Problem

Current adoptive cellular therapies for cancer face challenges due to T cell exhaustion mediated by the immunosuppressive tumor microenvironment, leading to hyporesponsiveness and limited persistence of immune effector cells.

Innovation Solution

The use of homing endonuclease variants and megaTALs that specifically cleave the human CBLB gene, allowing for genome editing to decrease or eliminate CBLB expression, thereby enhancing the persistence and efficacy of T cells in cancer immunotherapy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If adoptive cellular therapy is used to treat cancer, then T cell recognition and effector mechanisms are enhanced, but T cell exhaustion occurs due to the immunosuppressive tumor microenvironment

Engineering Contradiction:

ImproveT cell efficacyVSAvoidT cell persistence

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent extracts and removes the harmful CBLB gene from T cells through genome editing. By specifically targeting and eliminating CBLB expression, the invention removes the molecular mechanism that mediates T cell exhaustion, thereby resolving the contradiction between enhancing T cell efficacy and maintaining T cell persistence in the immunosuppressive tumor microenvironment

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the genetic parameter of T cells by editing the CBLB gene. This genetic modification fundamentally alters the T cell's response to the tumor microenvironment, transforming exhausted T cells into persistent, functional effector cells that can durably suppress cancer

Inventive Principle:

Principle #35Parameter changes

2Measurement precision

If T cells are exposed to the tumor microenvironment, then tumor recognition is enhanced, but immunosuppression leads to hyporesponsiveness

Engineering Contradiction:

ImproveTumor recognitionVSAvoidT cell responsiveness

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The patent converts the harmful effect of CBLB-mediated immunosuppression into a benefit by specifically targeting and eliminating CBLB through genome editing. The same tumor microenvironment exposure that previously caused exhaustion is transformed into a condition that selects for and enhances T cell functionality when CBLB is removed, thereby converting harm into benefit

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

Genome editing of the CBLB gene in T cells results in increased resistance to immunosuppression and T cell exhaustion, leading to more persistent and therapeutically efficacious immune responses against cancer.

Implementation Method 1

homing endonuclease variants and megaTALs that specifically cleave the human CBLB gene

Methodology Applied

Scientific EffectEnzymatic hydrolysis: Hydrolysis

Data Source

PatentUS20250179469A1CBLB endonuclease variants, compositions, and methods of use

Publication Date: 2025.06.05 REGENERON PHARMACEUTICALS INC

AI summary

The present disclosure provides improved genome editing compositions and methods for editing a casitas B-lineage (Cbl) lymphoma proto-oncogene B (CBLB) gene. The disclosure further provides genome edited cells for the prevention, treatment, or amelioration of at least one symptom of, a cancer, an infectious disease, an autoimmune disease, an inflammatory disease, or an immunodeficiency.